CN107021902A - A kind of levo-oxiracetam crystal formation I preparation method - Google Patents
A kind of levo-oxiracetam crystal formation I preparation method Download PDFInfo
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- CN107021902A CN107021902A CN201610064702.5A CN201610064702A CN107021902A CN 107021902 A CN107021902 A CN 107021902A CN 201610064702 A CN201610064702 A CN 201610064702A CN 107021902 A CN107021902 A CN 107021902A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
- C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/24—Oxygen or sulfur atoms
- C07D207/26—2-Pyrrolidones
- C07D207/273—2-Pyrrolidones with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to other ring carbon atoms
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Abstract
The present invention opens the route of a brand-new culture levo-oxiracetam monocrystalline, and with capillary tube method under the cooperation of specific solvent and humiture, so that levo-oxiracetam crystal formation I has successfully been made, the scientific research of levo-oxiracetam crystal formation has been promoted significantly.
Description
Technical field
The present invention relates to levo-oxiracetam, and in particular to a kind of levo-oxiracetam crystal formation I preparation method.
Background technology
Levo-oxiracetam (Oxiracetam) is nootropic agents of new generation, and pyrrolidinone compounds (ring GABOB) are derivative
Thing, Piracetam analog can promote Phosphorylcholine and adjacent acyl monoethanolamine synthesis, promote brain metabolism, by blood-brain barrier to spy
Different in nature central nervous pathway has stimulation, improves intelligence and memory.To cerebrovascular disease, brain damage, brain tumor (postoperative), encephalic sense
Dye, dementia, brain degenerative disease etc. have good efficacy.Suitable for light moderate vascular dementia, senile dementia and brain trauma
Deng memory and disturbance of intelligence caused by disease.Levo-oxiracetam was synthesized first by Italian SmithKline than Qie Mu company in 1974,
List within 1987, the concentration to memory especially thinking is more preferable than Piracetam, and toxicity is smaller, and research shows its levo form
Better efficacy, levo-oxiracetam structure is as follows：
For levo-oxiracetam is effectively developed into medicine, it is necessary to it is a kind of have easily fabricated and acceptable chemistry and
The solid-state form of physical stability, to promote its processing and circulation to store.For the purity and stability that strengthen compound,
Crystalline solid form generally to be preferred over armorphous form.Presently disclosed levo-oxiracetam crystal formation has tri- kinds of crystal formations of I, II, III,
Wherein crystal formation I has preferable stability.CN102249975A discloses a kind of levo-oxiracetam crystal formation I and its preparation side
Crystal formation I is made in method, levo-oxiracetam after water and acetone secondary crystallization, the crystal formation 12.500,13.940,15.000,
16.540,17.400,19.320,20.520,20.840,21.980,23.340,25.120,25.840,26.240,27.660,
28.100,30.040,30.660,31.040,31.780,34.300,35.180,37.060,38.020 and 42.240 degree of 2 θ
There is characteristic peak under angle, the levo-oxiracetam I that the preparation method according to the patent is obtained, crystal form purity (chemical purity)
99.3%, but its optical purity is in 98-99% or so.Prepared more the need in order to meet medical industry, it is necessary to develop one kind
High-optical-purity levo-oxiracetam I method.
The content of the invention
It is an object of the invention to provide a kind of levo-oxiracetam crystal formation I preparation method, this method preparation technology is simple,
Obtained product chiral purity is high.
Technical scheme involved in the present invention is as follows：
A kind of levo-oxiracetam crystal formation I preparation method, it is characterised in that use following steps：
Levo-oxiracetam is dissolved with organic solvent, then sucked by siphon among capillary, with capillary of sealing with wax
One end of pipe, is positioned over temperature for 30~50 DEG C, and humidity be to be volatilized in the air that RH (%) is 30%~50%, obtained left
Revolve Oxiracetam crystal form I；The organic solvent is tetrahydrofuran, pyridine, normal propyl alcohol or ethanol.
Above-mentioned ethanol is absolute ethyl alcohol.
The levo-oxiracetam crystal formation I that the present invention is prepared is 12.500,13.940,15.000 in the θ of angle of diffraction 2,
16.540,17.400,19.320,20.520,20.840,21.980,23.340,25.120,25.840,26.240,27.660,
28.100,30.040,30.660,31.040,31.780,34.300,35.180,37.060, have at 38.020 and 42.240 degree
Diffraction maximum, it is consistent with the crystal formation that CN102249975A is disclosed.
The present invention opens the route of a brand-new culture levo-oxiracetam monocrystalline, with capillary tube method specific molten
Under agent and the cooperation of humiture, so that levo-oxiracetam crystal formation I has successfully been made, promote levo-oxiracetam brilliant significantly
The scientific research and application of type.
In order to further improve the yield and purity of the present invention, the temperature preferably volatilized in air is 40~50 DEG C, humidity
It is 30%~40% for RH (%).
In order to further improve the purity of the present invention, the purity of raw material levo-oxiracetam of the present invention is more than 99.5%.
In order to ensure the purity of raw material, levo-oxiracetam can first be made by the following method, then pass through capillary
Levo-oxiracetam crystal formation I is made in method under given conditions, and specific reaction scheme is：
；
Operating procedure is：
1), first S-4- chloro-3-hydroxyls isopropyl isobutyrate is dissolved with isopropanol, then Azide is added at 80~90 DEG C
Sodium reaction obtains intermediate compound I for 3~4 hours, and wherein S-4- chloro-3-hydroxyls isopropyl isobutyrate and sodium azide mol ratio are 1：2~
3；
2) intermediate compound I is dissolved with methanol, carrying out reduction reaction with hydrogen by catalyst of Metal Palladium obtains intermediate II,
Reaction temperature is 0~20 DEG C, and the reaction time is 10~12 hours；
3) intermediate II is dissolved with methanol, potassium carbonate is catalyst, reacted 5~6 hours with benzyl acetate bromide, reaction temperature
40~60 DEG C of degree；The intermediate II and the mol ratio of benzyl acetate bromide are：1:1.5~2.5, intermediate II and the potassium carbonate
Mol ratio be：1:2~3；
4) intermediate III is dissolved with toluene, ring closure reaction is carried out under the conditions of 110~120 DEG C and obtains intermediate compound IV, instead
It is 6~7 hours between seasonable；
5) intermediate compound IV and concentrated ammonia liquor are reacted 11~15 hours at 20~30 DEG C, obtain levo-oxiracetam crude product,
The intermediate compound IV：The mol ratio of ammonia is intermediate compound IV：Ammonia=1：12~15, in terms of the ammonia in ammonia methanol solution, the ammonia
The concentration of water is 25-28%；
6) levo-oxiracetam crude product is dissolved by heating in water, activated carbon decolorizing is filtered to remove activated carbon, is concentrated under reduced pressure
Water removal, stops concentration when surplus water is adds 2~3 times of products weight, and 0~5 DEG C of sub-cooled crystallization obtains left-handed Aura
It is western smooth；
7) levo-oxiracetam is dissolved with organic solvent, then sucked by siphon among capillary, with hair of sealing with wax
One end of tubule, is positioned over temperature for 40~50 DEG C, and humidity be to be volatilized in the air that RH (%) is 30%~40%, obtained
Levo-oxiracetam crystal formation I；The organic solvent is tetrahydrofuran, pyridine, normal propyl alcohol or absolute ethyl alcohol.
The concentration of above-mentioned concentrated ammonia liquor is 25-28%.
The present invention uses S-4- chloro-3-hydroxybutanoic acid esters and sodium azide to prepare levo-oxiracetam, circuit letter for initiation material
Single, intermediate and product do not need the impurity for not produced in column chromatography, preparation process and being difficult to remove
Obtained levo-oxiracetam product chemistry purity reaches more than 99.5% through efficient liquid phase detection, then in specific solvent, temperature
Degree with the cooperation of humidity, levo-oxiracetam crystal formation I is prepared by capillary tube method, optical purity more than 99.9%,
Greatly improve levo-oxiracetam crystal formation I product quality.
Brief description of the drawings
Fig. 1 is levo-oxiracetam crystal formation I powder diagram；
Fig. 2 is levo-oxiracetam crystal formation I and crystal formation II differential scanning calorimeter figure (DSC)；
Fig. 3 is levo-oxiracetam crystal formation I Raman spectrogram；
Fig. 4 is levo-oxiracetam crystal formation I thermogravimetric analysis figure；
Fig. 5 is levo-oxiracetam crystal formation I circular dichroism spectrogram.
Embodiment
The present invention is specifically described below by embodiment, it is necessary to it is pointed out here that be that following examples are only used
It is further described in the present invention, it is impossible to be interpreted as limiting the scope of the invention, person skilled in art can
To make some nonessential modifications and adaptations to the present invention according to the invention described above content.
Embodiment 1
The levo-oxiracetam (20mg) that purity is more than 99.5% is dissolved with tetrahydrofuran (2mL), then passes through siphon
Suck among capillary, with the one end for capillary of sealing with wax, it is 40 DEG C to be positioned over temperature, humidity is the air that RH (%) is 30%
It is middle to be volatilized, levo-oxiracetam crystal formation is made.
Obtained levo-oxiracetam crystal formation is tested by X-ray powder diffraction, as a result such as Fig. 1, diffraction maximum is parsed such as
Following table：
The powder diffraction peak of various crystal formations
Obtained levo-oxiracetam crystal formation is 12.500,13.940,15.000,16.540 in the θ of angle of diffraction 2,
17.400,19.320,20.520,20.840,21.980,23.340,25.120,25.840,26.240,27.660,28.100,
There is diffraction maximum at 30.040,30.660,31.040,31.780,34.300,35.180,37.060,38.020 and 42.240 degree,
It is consistent with the crystal formation I that CN102249975A is disclosed.
The infrared spectrum that obtained levo-oxiracetam crystal formation I is produced shows absworption peak in following wave number：
Hydroxyl νO-H：(3403cm-1), acid amides νN-H(3355cm-1、3184cm-1), methylene νC-H(2926cm-1、2881cm-1), carbonyl νC=O(1672cm-1)、δCH2 (scissors)(1489cm-1), hydroxyl δO-H (in face)(1399cm-1), primary amide δN-H(1307cm-1)、δC-O(1082cm-1), primary amide δN-H (outside face)(672cm-1)。
Levo-oxiracetam crystal formation I made from embodiment 1 is subjected to optical purity measure：
Levo-oxiracetam crystal formation I is taken, precision weighs quantity (equivalent to containing levo-oxiracetam 120mg) and puts 100ml amounts
The solution of the 1.2mg containing levo-oxiracetam in every 1ml is made in bottle, plus mobile phase ultrasonic dissolution and constant volume, is used as need testing solution.
Precision measures solution 20ul, injects liquid chromatograph, records chromatogram, calculates unknown miscellaneous by area normalization method
The content of matter.
Determining chromatographic condition used is：
Instrument：Shimadzu LC-2010AHT high performance liquid chromatographs；
Work station title：LC-Solutio；
Chromatographic column：AGOP (4.6 × 100mm, 5 μm)；
Mobile phase:Acetonitrile：Phosphate buffer (pH6.0)=15:85；
Detection wavelength：210nm；
Flow velocity：1ml/min；
35 DEG C of column temperature；
Calculation formula is as follows：
In formula, Ai is the peak area of main ingredient active component levo-oxiracetam；
Σ A are the peak area sum of S- configurations and the oxo-1-pyrrolidine ethanamide of R- isomers 4- hydroxyls -2.
Through three measurements, average, the optical purity for obtaining the levo-oxiracetam crystal formation I of embodiment 1 is 99.96%.
For using capillary tube method carry out levo-oxiracetam crystal formation culture for, different solvents, volatilization temperature with
And the condition such as the humidity of air may cause different results.Such as following comparative example 1-3, air humidity is excessive, can not obtain
To single crystal form, it is levo-oxiracetam crystal formation I that humidity is smaller, volatilization temperature mismatched with humidity may obtain crystal formation I and
Crystal formation II mixture.
Comparative example 1
The levo-oxiracetam (20mg) that purity is more than 99.5% is dissolved with tetrahydrofuran (2mL), then passes through siphon
Suck among capillary, with the one end for capillary of sealing with wax, it is 40 DEG C to be positioned over temperature, humidity is the air that RH (%) is 90%
It is middle to be volatilized, levo-oxiracetam single crystal form as a result can not be made.
Comparative example 2
The levo-oxiracetam (20mg) that purity is more than 99.5% is dissolved with tetrahydrofuran (2mL), then passes through siphon
Suck among capillary, with the one end for capillary of sealing with wax, it is 40 DEG C to be positioned over temperature, humidity is the air that RH (%) is 70%
It is middle to be volatilized, be made levo-oxiracetam crystal formation, the crystal formation the θ of angle of diffraction 2 be 10.669,13.25,13.847,
14.198、16.729、17.934、18.746、18.816、20.273、20.413、21.431、21.617、21.663、23.38、
24.324、24.415、26.069、26.107、27.901、28.621、28.925、29.449、29.484、31.702、36.516、
37.685th, there is diffraction maximum at 39.721 degree, it is consistent with the levo-oxiracetam crystal formation II that CN102558013A is disclosed.
Change the solvents tetrahydrofurane in comparative example 2 into pyridine, normal propyl alcohol or absolute ethyl alcohol, remaining condition is constant, equally
Levo-oxiracetam single crystal form, and the levo-oxiracetam crystal formation II disclosed for CN102558013A can be made.
Comparative example 3
The levo-oxiracetam (20mg) that purity is more than 99.5% is dissolved for 95% ethanol (2mL) with concentration, then
Sucked by siphon among capillary, with the one end for capillary of sealing with wax, be positioned over temperature for 40 DEG C, humidity is that RH (%) is
Volatilized in 30% air, be made levo-oxiracetam crystal formation, the crystal formation the θ of angle of diffraction 2 be 10.669,13.25,
13.847、14.198、16.729、17.934、18.746、18.816、20.273、20.413、21.431、21.617、21.663、
23.38、24.324、24.415、26.069、26.107、27.901、28.621、28.925、29.449、29.484、31.702、
36.516th, 37.685, there is diffraction maximum at 39.721 degree, it is consistent with the levo-oxiracetam crystal formation II that CN102558013A is disclosed.
Further experiment is found, when solvent is 95% ethanol, and air humidity be RH (%) under the conditions of 30%~70,
Levo-oxiracetam single crystal form can be made, but is the levo-oxiracetam crystal formation II that CN102558013A is disclosed.
Comparative example 4
The levo-oxiracetam (20mg) that purity is more than 99.5% is dissolved with tetrahydrofuran (2mL), then passes through siphon
Suck among capillary, with the one end for capillary of sealing with wax, it is 80 DEG C to be positioned over temperature, humidity is the air that RH (%) is 70%
It is middle to be volatilized, levo-oxiracetam crystal formation is made, is the mixed of levo-oxiracetam crystal formation I and crystal formation II by Structural Identification
Compound.
Embodiment 2
(l) preparation of intermediate compound I：
Raw material S-4- chloro-3-hydroxyl isopropyl isobutyrate 5g are taken, is added in a single neck bottle, is added isopropanol 10ml, stir, plus
Enter sodium azide 5g, reacted 3 hours at 85 DEG C or so after adding, yellow solution is reacted to obtain in stopping.Water 20ml is added, acetic acid second is used
Ester 20ml is extracted, and concentration removes ethyl acetate, obtains yellow oil intermediate compound I.Detected through nuclear-magnetism, intermediate compound I is：1H-NMR
(300MHz,CDCl3):1.35-1.73(m,8H)2.76-2.67(AB system,m,2H,),3.31-3.23(AB system,
M, 2H), 4.31 (m, 1H), 4.40 (m, 1H), 3.70 (s, 1H) intermediate compound Is are：
(2) preparation of intermediate II
The intermediate compound I that step (1) is obtained is dissolved in 50ml methanol, is cooled to outer 5 DEG C or so of temperature, adds 10% palladium
C catalyst 1.3g, is passed through stirring under hydrogen 12 hours, and point plate is shown in that raw material reaction is complete, stops reaction, and concentration removes solvent and obtained
To pale yellow oil intermediate II.Detected through nuclear-magnetism, intermediate II：1.35 (m, 6H), 2.76-2.67 (AB system, m,
2H,),3.31-3.23(AB system,m,2H),4.31(m,1H),4.40(m,1H),4.70(bs,3H)
Intermediate II is
(3) preparation of intermediate III
The intermediate II that step (2) is obtained is dissolved in 50ml methanol, and potassium carbonate (3eq) is added at 40 DEG C or so,
There are a large amount of solids to generate, stir five minutes, start that benzyl acetate bromide (2eq) is added dropwise, dropwise addition process has exothermic phenomenon, completion of dropping
Continue to stir 6 hours or so afterwards, point plate is shown in that raw material reaction is complete, stops reaction, adds EA (ethyl acetate) 50ml, water 30ml,
Solid is completely dissolved, by water layer solid sodium chloride saturation, separates organic layer, and water layer is extracted twice with EA 20ml, is merged organic
Layer, organic layer washed three times with 2M hydrochloric acid 20ml, merges hydrochloric acid aqueous phase, and organic phase is discarded, aqueous phase with sodium acid carbonate adjust pH to
8, solid sodium chloride saturation, EA 30ml are extracted three times, merge organic phase, and anhydrous magnesium sulfate is dried, and concentration removes solvent and obtains light
Yellow oil, curing at low temperatures obtains intermediate III.Detected through nuclear-magnetism, intermediate III：1H-NMR(300MHz,D2O):1.35
(m,6H),2.28-2.53(m,2H),2.58-2.83(m,2H)3.51(s,2H),4.09-4.22(m,2H),5.34(m,2H)
7.05-7.23(m,5H).
Intermediate III is
(4) preparation of intermediate compound IV
The intermediate III that step (2) is obtained 50ml toluene dissolves, and is warming up to 115 DEG C or so and reacts 5 hours, obtains one
Red tan solution, point plate is shown in that raw material reaction is complete.Stop reaction, concentration removes toluene, add EA (ethyl acetate) dissolvings, filtering
Except desalting, activated carbon decolorizing, concentration remove yellow oil obtains intermediate compound IV.Detected through nuclear-magnetism, intermediate compound IV is：1H-
NMR(300MHz,CDCl3)2.38(dd,1H),2.69(dd,1H),3.34(dd,1H),3.77(dd,lH),3.93(d,lH),
4.18 (d, 1H), 4.30 (bs, 1H), 4.50 (m, 1H), 5.34 (s, 2H), 7.05-7.26 (m, 5H)
Intermediate compound IV：
(5) preparation of (S)-Oxiracetam
The intermediate compound IV that step (4) is obtained adds concentrated ammonia liquor (concentration is 25%) 20ml, is stirred at room temperature 13 hours, puts plate
See that raw material reaction is complete, stop reaction, water removal and ammonia are removed in concentration, obtain yellow oil, add acetone solution grease, plus
Enter a small amount of crystal seed to stir, precipitation solid, a small amount of acetone rinsing bottle wall, -10 DEG C crystallize 5 hours, are filtrated to get off-white color crude product
22.5g, chemical purity 98.7%.
(6) by the dissolving crude product in 100ml water, heating dissolves it, activated carbon decolorizing half an hour, is filtered to remove work
Property charcoal, crystallisation by cooling, 5 DEG C are stood overnight, and next day filters to obtain to be free of in white solid 20.2g, chemical purity 99.5%, end-product
HaveDetected through nuclear-magnetism, (S)-Oxiracetam：1H-NMR(300MHz,DMSO-d6)δ2.10
(d,1H),2.57(dd,1H),3.69(d,1H),3.88(d,1H),4.10(d,1H),4.31(m,1H),5.25(s,1H),
7.13(s,1H),7.33(s,1H)。
(S)-Oxiracetam structural formula is as follows：
(7) levo-oxiracetam crystal formation I preparation：
Levo-oxiracetam (70mg) made from step (5) is dissolved with normal propyl alcohol (5mL), hair is then sucked by siphon
Among tubule, with the one end for capillary of sealing with wax, it is 40 DEG C to be positioned over temperature, and humidity is progress in the air that RH (%) is 45%
Volatilization, is made levo-oxiracetam crystal formation, is verified by X powder diffraction, identical with crystal formation I made from embodiment 1, and optical voidness
Spend for 99.90%.
Embodiment 3-5 is made with reference to embodiment 2, partial parameters are according to following operation：
(S)-Oxiracetam chemical purity made from embodiment 3-5 is high, wherein not containing
Chemical purity more than 99.5% can be achieved in general purification (being handled without column chromatography), as crystalline substance of the raw material with reference to embodiment 1
Type culture, is successfully made (S)-Oxiracetam crystal form I, and its optical purity is more than 99.90%.
Embodiment 6
The levo-oxiracetam (100mg) that purity is more than 99.6% is dissolved with tetrahydrofuran (5mL), then passes through siphon
Suck among capillary, with the one end for capillary of sealing with wax, it is 45 DEG C to be positioned over temperature, humidity is the air that RH (%) is 35%
It is middle to be volatilized, levo-oxiracetam crystal formation is made, is verified with X powder diffraction method, obtained crystal formation and the crystal formation I of embodiment 1
It is identical, and optical purity is 99.93%.
Embodiment 7
Purity is dissolved by heating for 99.5% levo-oxiracetam (300mg) with normal propyl alcohol (10mL), then passes through rainbow
Among suction capillary, with the one end for capillary of sealing with wax, it is 35 DEG C to be positioned over temperature, and humidity is the sky that RH (%) is 30%
Volatilized in gas, levo-oxiracetam crystal formation is made, verified with X powder diffraction method, obtained crystal formation and the crystal formation of embodiment 1
I is identical, and optical purity is 99.95%.
Embodiment 8
99.5% levo-oxiracetam (80mg) is dissolved with absolute ethyl alcohol (10mL), capillary is then sucked by siphon
Among pipe, with the one end for capillary of sealing with wax, it is 60 DEG C to be positioned over temperature, and humidity be RH (%) to be waved in 40% air
Hair, is made levo-oxiracetam crystal formation, verifies that obtained crystal formation is identical with the crystal formation I of embodiment 1, and light with X powder diffraction method
It is 99.90% to learn purity.
Claims (4)
1. a kind of levo-oxiracetam crystal formation I preparation method, it is characterised in that use following steps：
Levo-oxiracetam is dissolved with organic solvent, then sucked by siphon among capillary, with capillary of sealing with wax
One end, is positioned over temperature for 30~50 DEG C, and humidity be to be volatilized in the air that RH (%) is 30%~50%, obtained left-handed Austria
La Xitan crystal formations I；The organic solvent is tetrahydrofuran, pyridine, normal propyl alcohol or absolute ethyl alcohol；The levo-oxiracetam crystal formation
I is 12.500,13.940,15.000,16.540,17.400,19.320,20.520,20.840 in the θ of angle of diffraction 2,
21.980,23.340,25.120,25.840,26.240,27.660,28.100,30.040,30.660,31.040,31.780,
34.300,35.180,37.060,38.020 with 42.240 degree at have diffraction maximum.
2. the method as described in claim 1, it is characterised in that：The temperature volatilized in air is 40~50 DEG C, and humidity is RH
(%) is 30%~40%.
3. method as claimed in claim 1 or 2, it is characterised in that：The purity of the levo-oxiracetam is more than 99.5%.
4. the method as described in claim 1, it is characterised in that：First pass through following route and levo-oxiracetam, Ran Houyong is made
Levo-oxiracetam crystal formation I is made in capillary tube method；Reaction scheme is：
；
Operating procedure is：
1), first S-4- chloro-3-hydroxyls isopropyl isobutyrate is dissolved with isopropanol, sodium azide is then added at 80~90 DEG C anti-
Answer and obtain within 3~4 hours intermediate compound I, wherein S-4- chloro-3-hydroxyls isopropyl isobutyrate and sodium azide mol ratio are 1：2~3；
2) intermediate compound I is dissolved with methanol, carrying out reduction reaction with hydrogen by catalyst of Metal Palladium obtains intermediate II, reacts
Temperature is 0~20 DEG C, and the reaction time is 10~12 hours；
3) intermediate II is dissolved with methanol, potassium carbonate is catalyst, reacted 5~6 hours with benzyl acetate bromide, reaction temperature 40
~60 DEG C；The intermediate II and the mol ratio of benzyl acetate bromide are：1:1.5~2.5, intermediate II is rubbed with the potassium carbonate
You are at ratio：1:2~3；
4) intermediate III is dissolved with toluene, ring closure reaction is carried out under the conditions of 110~120 DEG C and obtains intermediate compound IV, during reaction
Between be 6~7 hours；
5) intermediate compound IV and ammoniacal liquor are reacted 11~15 hours at 20~30 DEG C, obtain levo-oxiracetam crude product, it is described in
Mesosome IV：The mol ratio of ammonia is intermediate compound IV：Ammonia=1：12~15, in terms of the ammonia in ammonia methanol solution, the ammoniacal liquor it is dense
Spend for 25-28%；
6) levo-oxiracetam crude product is dissolved by heating in water, activated carbon decolorizing is filtered to remove activated carbon, is concentrated under reduced pressure and removes
Water, stops concentration when surplus water is adds 2~3 times of products weight, and 0~5 DEG C of sub-cooled crystallization obtains left-handed Aura west
It is smooth；
7) levo-oxiracetam is dissolved with organic solvent, then sucked by siphon among capillary, with capillary of sealing with wax
One end, be positioned over temperature for 40~50 DEG C, humidity be to be volatilized in the air that RH (%) is 30%~40%, obtained left-handed
Oxiracetam crystal form I；The organic solvent is tetrahydrofuran, pyridine, normal propyl alcohol or absolute ethyl alcohol.
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| CN201610064702.5A Withdrawn CN107021902A (en) | 2016-01-29 | 2016-01-29 | A kind of levo-oxiracetam crystal formation I preparation method |
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102249975A (en) * | 2010-05-21 | 2011-11-23 | 重庆润泽医疗器械有限公司 | (S)-4-hydroxy-2-oxo-1-pyrrolidineacetamide crystal form I and preparation method and application thereof |
| CN104230777A (en) * | 2013-06-19 | 2014-12-24 | 成都百途医药科技有限公司 | Synthetic method of oxiracetam |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102249975A (en) * | 2010-05-21 | 2011-11-23 | 重庆润泽医疗器械有限公司 | (S)-4-hydroxy-2-oxo-1-pyrrolidineacetamide crystal form I and preparation method and application thereof |
| CN104230777A (en) * | 2013-06-19 | 2014-12-24 | 成都百途医药科技有限公司 | Synthetic method of oxiracetam |
Non-Patent Citations (1)
| Title |
|---|
| ENGIN SAHIN, ET AL.: "AN EFFICIENT SYNTHESIS OF (R)-GABOB AND OF (±)-GABOB", 《ORGANIC PREPARATIONS AND PROCEDURES INT.》 * |
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